The present invention relates to enhancing the inhibition of T-cell proliferation in a mammalian host and especially a human host. More particularly, the present invention is concerned with enhancing the inhibition of T-cell proliferation by administering 2xe2x80x2-deoxyguanosine and/or prodrugs thereof and certain PNP inhibitors which significantly prolong the half-life of the 2xe2x80x2-deoxyguanosine in a host. The PNP inhibitors employed according to the present invention are disclosed in U.S. Pat. No. 5,985,848 to Schramm et al., entitled xe2x80x9cPurine Nucleoside Phosphorylase Inhibitors,xe2x80x9d disclosure of which is incorporated herein by reference. The process of the present invention enhances the selective inhibition of T-cell proliferation without damaging humoral immunity, which renders the process potentially effective against disorders in which T-cells are pathogenic.
Purine nucleoside phosphorylase (PNP) deficiency is a rare inherited disease accounting for approximately 4% of patients with severe combined immunodeficiency. In PNP deficiency, T- and B-cell immunity are affected. T-cell function may be profoundly deficient, may be normal at birth and then decrease with time, or may fluctuate repeatedly between low and normal. B-cell function can be normal but is deficient in approximately one third of patients. PNP protein is a trimer of approximately 90,000 daltons. It is found in most tissues of the body but is at highest levels in lymphoid tissues. This tissue distribution explains why the lymphoid system is predominantly affected in PNP deficiency. Many mechanisms have been proposed to explain the metabolic toxicity in PNP deficiency. The elevated dGTP found in PNP deficiency is thought to inhibit ribonucleotide reductase and, thus, impede cell division.
8-Aminoguanine given with 2xe2x80x2-deoxyguanosine inhibits the proliferation of human T-cells (CCRF-CEM and Molt-4 cells) in cultures. 8-Aminoguanosine, a soluble derivative which is converted in vivo to 8-aminoguanine, given to rats and dogs with 2xe2x80x2-deoxyguanosine causes a profound fall in peripheral blood lymphocytes and was shown in rats to produce increased levels of 2xe2x80x2-deoxyguanosine triphosphate (dGTP) in T-cells. To produce lymphopenia, inhibition of PNP was required, since 2xe2x80x2-deoxyguanosine alone did not significantly decrease cell counts.
(1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol is one of a family of potent PNP inhibitors. This application provides for administration of exogenous 2xe2x80x2-deoxyguanosine in addition to the PNP inhibitor, which would cause a sufficient accumulation of dGTP exclusively in the T-cells to prevent their proliferation. However, exogenous 2xe2x80x2-deoxyguanosine rapidly degrades upon being administered to a host and therefore is not effective when administered alone. Accordingly, efforts have been underway to discover procedures for significantly prolonging its half-life in a host in order to achieve sufficient accumulation of dGTP in T-cells preventing their proliferation.
It has been found according to the present invention that administering certain PNP inhibitors in addition to the exogenous 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine results in significantly prolonging the half-life of the 2xe2x80x2-deoxyguanosine. Therefore, the combination of 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine and the PNP inhibitors employed according to the present invention provides a potentially effective treatment against disorders in which activated T-cells are pathogenic. For instance, T-cell lymphomas and T-cell leukemias (such as acute lymphoblastic leukemia) maybe treated with a combination of a PNP inhibitor and exogenous 2xe2x80x2-deoxyguanosine and/or prodrug. T-cells have also been implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and type 1 diabetes. This association strongly suggests that the present invention will be an effective therapy for these diseases. Another indication amenable to the treatment described is graft versus host disease (GVHD).
The PNP inhibitors employed according to the present invention are disclosed in U.S. Pat. No. 5,985,848. The PNP inhibitors employed according to the present invention also have a Ki value of about 500 picomolar or less. The PNP inhibitor can be administered along with or prior to the 2xe2x80x2-deoxyguanosine and/or prodrug of 2xe2x80x2-deoxyguanosine.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.